Maintenance paradigm in non-squamous NSCLC

Transcription

1 Maintenance paradigm in non-squamous NSCLC L. Paz-Ares Hospital Universitario Virgen del Rocío Sevilla

2 Agenda Theoretical basis The data The comparisons

3 Agenda Theoretical basis The data The comparisons

4 Pro Continuation Maintenance

5 Pro Continuation Maintenance Why Maintenance Why Continuation

6 Pro Continuation Maintenance Why Maintenance - may have disease under control Why Continuation

7 Maintenance in advanced NSCLC: Treating Before Disease Progression Until Progression or Intolerance Traditional approach 1 st -line treatment platinum doublet chemotherapy (4 6 cycles) Break from treatment 2 nd /3 rd line treatment Diagnosis CR/PR/SD PD PD Maintenance approach Maintenance therapy Increased time to PD Diagnosis CR/PR/SD PD PD

8 Maintenance in Other Chronic Diseases Other Cancers Breast Colorectal Prostate Mesothelioma Respiratory Diseases COPD Granulomatosis Lupus Fibrosis

9 Pro Continuation Maintenance Why Maintenance - may have disease under control Why Continuation - if you are using a different drug, this is not maintenance

10 Maintenance treatment Types Continuation therapy: Prolonged platinum doublet chemotherapy Continuation Maintenance: Continuation of non-platinum agent used in doublet chemotherapy e.g. paclitaxel, gemcitabine, pemetrexed Switch Maintenance: Introduction of a new cytotoxic agent e.g. docetaxel, pemetrexed, erlotinib Stinchcombe, TE et al. J Thoracic Oncol 2009;4:243 50

11 Pro Continuation Maintenance Why Maintenance - may have disease under control Why Continuation - if you are using a different drug, this is not maintenance - we should squeeze the benefit for any single drug

12 Pro Continuation Maintenance Why Maintenance - may have disease under control Why Continuation - if you are using a different drug, this is not maintenance - we should squeeze the benefit for any single drug - continuation maintenance is standard in most oncological contexts (including targeted therapy in lung cancer)

13 Agenda Theoretical basis The data The comparisons

14 Switch Maintenance With Docetaxel Patients without disease progression randomized 1:1 Chemotherapynaive patients with stage IIIB/IV NSCLC (N = 566) Gemcitabine/Carboplatin for 4 cycles Immediate Docetaxel (n = 153) Delayed Docetaxel* (n = 156) *Initiated at first evidence of progressive disease Primary endpoint: OS Other endpoints: PFS, ORR, safety, QOL Fidias PM, et al. J Clin Oncol. 2009;27:

15 Probability of PFS Docetaxel Switch Maintenance: PFS HR=0.71 (95% CI: ) p< Delayed Immediate Mos Patients at Risk, n Delayed Immediate Median PFS delayed vs immediate: 2.7 vs 5.7 mos (P =.0001) 48 Fidias PM, et al. J Clin Oncol. 2009;27:

16 Probability of OS Docetaxel Switch Maintenance: OS Delayed Immediate HR=0.84 (95% CI: ) p< Mos Patients at Risk, n Delayed Immediate Median OS delayed vs immediate: 9.7 vs 12.3 mos (P =.0853) 1-yr survival delayed vs immediate: 43.5% vs 51.1% 60 Fidias PM, et al. J Clin Oncol. 2009;27:

17 JMEN Study Design Double-blind, multicenter, placebo-controlled, phase III trial Randomized 2:1 according to sex, PS, stage, best response, nonplatinum drug, brain metastases Patients with stage IIIB/IV NSCLC, ECOG PS 0-1, 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD (N = 663) Pemetrexed 500 mg/m 2 (d1,q21d) + BSC (n = 441)* Placebo (d1, q21d) + BSC (n = 222)* Primary endpoint: PFS *B 12, folate, and dexamethasone given in both arms Cielanu et al., Lancet 2010

18 Probability Maintenance pemetrexed (JMEN): PFS and OS PFS (n=581) OS (n=663) 1.0 Pemetrexed: 4.0 months 1.0 Pemetrexed: 13.4 months Placebo: 2.0 months Placebo: 10.6 months HR=0.599 (95% CI: ) p< HR=0.79 (95% CI: ) p= Time (months) Time (months) Cielanu et al., Lancet 2010

19 Maintenance pemetrexed (JMEN): PFS (n=581) OS (n=663) Cielanu et al., Lancet 2010

20 SATURN: Erlotinib maintenance Erlotinib 150mg/day PD Chemonaïve advanced NSCLC (n=1,949) 4 cycles of 1st-line platinumbased doublet Non-PD (n=889) 1:1 Placebo PD Mandatory tumour sampling Co-primary endpoints PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL) Cappuzzo, et al. WCLC 2009

21 PFS probability PFS: Erlotinib versus placebo (ITT) 1.0 Erlotinib (n=437) Placebo (n=447) PFS at 12 weeks (%) PFS at 24 weeks (%) HR=0.71 ( ) Log-rank p< Time (weeks) Cappuzzo, et al. WCLC 2009

22 OS probability OS: Erlotinib versus placebo (ITT) Erlotinib (n=438) Placebo (n=451) HR=0.81 ( ) Log-rank p= Time (months) Cappuzzo, et al. WCLC 2009

23 Advanced NSCLC: Gemcitabine Maintenance Therapy Primary endpoint: PFS Chemotherapy-naive patients with stage IIIB/IV NSCLC and CR / PR / SD after cisplatin + gemcitabine (N = 206) Maintenance gemcitabine 1250 mg/m 2 Days 1, 8 Q3W plus BSC (n = 138) BSC only (n = 68) Brodowicz T, et al. Lung Cancer. 2006;52:

24 Advanced NSCLC: Gemcitabine Maintenance Therapy PFS PFS from the date of starting first-line PFS from the date of randomization HR=0.69 (95% CI: ) p<0.001 OS: 13.0 mos vs 11.0 mos, P =.195 Brodowicz T, et al. Lung Cancer. 2006;52:

25 Gemcitabine Maintenance + BSC vs BSC Alone Patients without disease progression randomized 1:1 Chemotherapynaive patients with stage IIIB/IV NSCLC (N = 519) Gemcitabine/Carboplatin for 4 cycles Gemcitabine + BSC (n = 128) BSC (n = 127) Patients stratified by PS, stage, best tumor response Primary endpoint: OS Other endpoints: PFS, ORR, safety Belani CP, et al. ASCO Abstract 7506.

26 Advanced NSCLC: Gemcitabine Maintenance Therapy PS 2 Belani CP, et al. ASCO Abstract 7506.

27 IFCT-GFPC 0502: Gemcitabine vs Erlotinib vs Observation as Maintenance Patients stratified by sex, histology, smoking status, treatment center, and response/stabilization following first-line therapy Primary endpoint: PFS Other endpoints: OS, safety, symptom control, effect of EGFR status Patients without disease progression randomized 1:1:1 Chemotherapynaive patients with stage IIIB/IV NSCLC Cisplatin/Gemcitabine for 4 cycles Gemcitabine (n = 154) Erlotinib (n = 155) (N = 834) Observation (n = 155) Perol M et al. ASCO 2010: Abstract 7507

28 Gemcitabine or Erlotinib Maintenance PFS Pérol M et al. JCO 2012;30:

29 Gemcitabine or Erlotinib Maintenance Overall survival Pérol M et al. JCO 2012;30:

30 Pemetrexed Maintenance v Placebo in Nonsquamous NSCLC: Phase III Study Patients without disease progression randomized 2:1 Chemotherapynaive patients with stage IIIB/IV nonsquamous NSCLC (N = 900 planned) Pemetrexed/Cisplatin for 4 cycles Pemetrexed + BSC Placebo + BSC Primary endpoint: PFS Other endpoints: OS, ORR, patient-reported outcomes, resource utilization, toxicity Paz-Ares LG, et al. BMC Cancer. 2010;10:85.

31 Survival Probability PARAMOUNT: PFS from Randomization PFS: Primary Efficacy Endpoint PFS: Reassessed at Time of Final OS Survival Probability Pemetrexed Placebo Unadjusted HR: 0.62 ( ) Time (Months) Patients at Risk Pem + BSC Plac+ BSC Patients at Risk Pemetrexed Placebo Unadjusted HR: 0.60 ( ) Time (Months) Pem +BSC Plac + BSC

32 Survival Probability PARAMOUNT: Final OS from Randomization Pemetrexed Placebo Unadjusted HR: 0.78 (95% CI: ); P= Time from Randomization (Months)

33 PARAMOUNT: Post-discontinuation Therapy Pemetrexed (N=359) %* Placebo (N=180) %* Patients Receiving Post Discontinuation Therapy Erlotinib Docetaxel Gemcitabine 10 8 Vinorelbine 8 6 Investigational drug 6 4 Carboplatin 5 4 Paclitaxel 3 3 Pemetrexed 2 4 Cisplatin 1 2

34 Survival probability Survival probability PARAMOUNT: OS Hazard Ratios by subgroups Hazard Ratio CR/PR HR = 0.81 All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker )n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age > 70 (n=92) Age < 65 (n=350) Age > 65 (n=189( Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) SD HR = Treatment Hazard Ratio (95%% CI) Time from Randomization (Months) Favors Pemetrexed Favors Placebo

35 PARAMOUNT: Possible Drug-related CTCAEs* Pemetrexed (N=359) Grade 1/2 % Grade 3/4 % Placebo (N=180) Grade 1/2 % Grade 3/4 % Fatigue Nausea Anemia Vomiting Mucositis/stomatitis Neuropathy/sensory Neutropenia Leukopenia ALT (SGPT)

36 PARAMOUNT: Possible Drug-related CTCAEs* Pemetrexed (N=359) Grade 1/2 % Grade 3/4 % Placebo (N=180) Grade 1/2 % Grade 3/4 % Fatigue Nausea Anemia Vomiting Mucositis/stomatitis Neuropathy/sensory Neutropenia Leukopenia ALT (SGPT)

37 AVAPEARL1 Trial Pemetrexed Maintenance v Bevacizumab in Nonsquamous NSCLC: Phase III Study Patients without disease progression randomized 1:1 Chemotherapynaive patients with stage IIIB/IV nonsquamous NSCLC (N = 348) Pemetrexed/Cisplatin/ Bevacizumab for 4 cycles Pemetrexed + Bevacizumab Bevacizumab Primary endpoint: PFS Other endpoints: OS, ORR, QoL, toxicity Available from AVAPERL&rank=1. Accessed 19 March 2012.

38 Progression -free survival from date of randomization(%) AVAPERL: PFS From Randomization a Bev+pem 7.4 months (81 events) Bev 3.7 months (104 events) HR, 0.48 ( ); P <.001 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) Pts at risk 0 Bev+pem Bev Time (months) a Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm) bev, bevacizumab; cont., continuation; HR, hazard ratio; ITT, intent to treat; pem, pemetrexed; pts, patients. Barlesi et al., ESMO 2011

39 Agenda Theoretical basis The data The comparisons

40 Efficacy: PFS & OS Trial Switch Maintenance N Maintenance drug PFS HR (95% CI) OS HR (95% CI) Westeel et al. 181 Vinorelbine 0.77 ( ) 1.08 ( ) Fidias et al. 309 Docetaxel 0.71 ( ) 0.84 ( ) Capuzzo 889 Erlotinib 0.71 ( ) 0.81 ( ) Ciuleanu et al. 663 Pemetrexed 0.60 ( ) 0.79 ( ) Continuation Maintenance Paz-Ares et al 539 Pemetrexed 0.62 ( ) 0.78 ( ) Brodowicz et al. 206 Gemcitabine 0.69 ( ) 0.84 ( ) Belani et al. 255 Gemcitabine 1.09 ( ) 0.97 ( ) Perol et al. 309 Gemcitabine 0.56 ( ) 0.89 ( )

41 Efficacy: QOL Trial N Maintenance drug QoL & Symptom Control Switch Chemotherapy Maintenance Westeel et al. 181 Vinorelbine NR Fidias et al. 309 Docetaxel No differences Capuzzo 889 Erlotinib Better pain control Cieleanu et al. 663 Pemetrexed Better pain and hemoptisis control Continuation Chemotherapy Maintenance Paz-Ares et al 539 Pemetrexed No detrimental effect Brodowicz et al. 206 Gemcitabine NR Belani et al. 255 Gemcitabine NR Perol et al. 309 Gemcitabine NR

42 PARAMOUNT Induction vs JMDB Median number of induction cycles Response: Response Rate (CR/PR) Disease control rates (CR/PR/SD) PARAMOUNT Induction 4 cycles then pemetrexed maintenance 30.1% 74.5% JMDB 1 st -line treatment with 6 cycles 28.6% 63.8% Toxicity Laboratory toxicities Nonlaboratory toxicities Possibletreatment-related deaths Serious adverse events Supportive care 13.7% 14.8% 1.2% 14.2% almost the same More colony-stimulating factors in PARAMOUNT 21.4% 21.9% 1.0% 16.4% More anti-emetics use in JMDB G Scagliotti et al, abstr 203. WCLC 2011

43 Perol M. Poster presented at ESMO 2010: PD370 Toxicity: Grade III-IV Events

44 Consistent PFS and OS Results in JMEN & Saturn Studies: Greater Benefit in Patients With SD Versus CR/PR SATURN OS JMEN OS ITT population (n=889) CR/PR (n=394) SD (n=487) ITT population (n=663) CR/PR (n=322) SD (n=337) HR Favours Erlotinib Favours placebo HR Favours pemetrexed Favours placebo Cappuzzo F et al Lancet Oncol 11: Belani CP, et al. ASCO 2009 (Abs. CRA8000)

45 Gemcitabine or Erlotinib Maintenance PFS Pérol M et al. JCO 2012;30:

46 Survival probability Survival probability PARAMOUNT: OS Hazard Ratios by subgroups Hazard Ratio CR/PR HR = 0.81 All Randomized Patients (N=539) Stage IV (n=490) Stage IIIB (n=49) Induction Response CR/PR (n=234) Induction Response SD (n=285) Pre-randomization ECOG PS 1 (n=363) Pre-randomization ECOG PS 0 (n=173) Non-smoker (n=117) Smoker )n=418) Male (n=313) Female (n=226) Age < 70 (n=447) Age > 70 (n=92) Age < 65 (n=350) Age > 65 (n=189( Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) SD HR = Treatment Hazard Ratio (95%% CI) Time from Randomization (Months) Favors Pemetrexed Favors Placebo

47 Summary Maintenance therapy offers the possibility of continued active treatment to delay disease progression and symptom deterioration Continuation maintenance represents true maintenance. Available data with pemetrexed are relevant and robust (and not inferior to those of switch maintenance), and claim for a change in the treatment paradigm Studies with other compounds and histology are warranted Further studies are ongoing